5DRP

Structure of the AaLpxC/LPC-023 Complex

5DRP の概要

• エントリーDOI: 10.2210/pdb5drp/pdb
• 関連するPDBエントリー: 5DRO 5DRQ 5DRR
• 分子名称: UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, ZINC ION, N~2~-{4-[4-(4-aminophenyl)buta-1,3-diyn-1-yl]benzoyl}-N-hydroxy-L-isoleucinamide, ... (6 entities in total)
• 機能のキーワード: lpxc, inhibitor, lipid a, gram-negative bacteria, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Aquifex aeolicus (strain VF5)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63653.03

構造登録者

Najeeb, J.,Lee, C.-J.,Zhou, P. (登録日: 2015-09-16, 公開日: 2016-03-09, 最終更新日: 2023-09-27)

主引用文献

Lee, C.J.,Liang, X.,Wu, Q.,Najeeb, J.,Zhao, J.,Gopalaswamy, R.,Titecat, M.,Sebbane, F.,Lemaitre, N.,Toone, E.J.,Zhou, P.
Drug design from the cryptic inhibitor envelope.
Nat Commun, 7:10638-10638, 2016

PubMed Abstract: Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.

PubMed: 26912110
DOI: 10.1038/ncomms10638

実験手法

X-RAY DIFFRACTION (1.889 Å)